[Sporadic kidney cancer of young subjects: Study of the clinical and pathological features of a bicentric cohort]. / Le cancer du rein sporadique du sujet jeune : étude des particularités cliniques et anatomopathologiques d'une cohorte bicentrique.

INTRODUCTION: The epidemiology of kidney cancer is evolving with a net increase in the incidence of renal tumors, globally, and in young people in particular. OBJECTIVE: To evaluate the incidence and clinical and pathological characteristics of sporadic renal tumors in young subjects and their risk factors. MATERIAL AND METHODS: A retrospective study aimed at collecting clinical, epidemiological and anatomopathological information from the 118 patients aged 18 to 40 treated for a sporadic kidney tumor in two Parisian university hospital centers between 2003 and 2013. RESULTS: Our study showed a very significant increase in the incidence of renal tumors in our 11 years of decline (P=6.10-15). The mode of discovery also seems to have evolved with a majority of tumors (67 %), due to the considerable growth of imaging in recent decades. We also showed a different pathological distribution compared to the literature with a significant increase in the number of papillary tumors (16.9 %) and chromophobes (15.2 %), in addition to a decrease in the number of carcinomas (43.2 %) as well as the appearance of a new pathological entity of particular clinical severity: renal carcinoma related to translocation Xp11.2 (15.3 %) (P<10-5). Among the risk factors, hypertension seems to be a definite risk factor while tobacco and obesity do not have a significant influence. CONCLUSION: Our study showed a marked increase in the incidence of renal tumors with specific clinical and epidemiological features in a population of young subjects. The role and importance of oncogenetic management as well as the study of environmental factors could lead to the identification of new risk factors and corollary to their prevention. LEVEL OF EVIDENCE: 4.

Nephron sparing surgery in tumours greater than 7cm.

INTRODUCTION: Partial nephrectomy (PN) is the gold standard treatment for renal cell carcinomas under 4cm. No robust data exists to recommend PN for tumours>7cm (cT2). The objective of this work is to evaluate the results of PN for cT2 tumours. PATIENTS AND METHODS: All patients who underwent PN or radical nephrectomy (RN) for cT2 tumours between 2000 and 2013 at our institution have been included. Patient demographics, postoperative data including renal function, morbidity, mortality and oncologic outcomes were reviewed retrospectively and compared using χ2 test, Mann-Whitney test, Kaplan-Meier method and log rank test. RESULTS: We included 130 patients, 49 (38%) in the PN group and 81 (62%) in the RN group, with a median follow-up of 42 months [19-69]. Variation of postoperative renal function at day 5 and last recorded value was significantly different between the groups (P=0.03 and P<0.001). The PN group had a significantly higher complication rate as compared with RN group (37% versus 14%, P=0.002). There were no significant differences between the two groups for overall, recurrence free and specific survival (P=0.55, P=0.55, P=0.24, respectively). In univariate analysis, the type of surgery (PN versus RN) was not associated with a significant difference of oncologic outcome (margins, survival). CONCLUSION: PN can be offered for cT2 tumours with oncological outcomes similar to RN. Despite an increased morbidity, it remains acceptable with the demonstrated advantage of preservation of renal function. LEVEL OF EVIDENCE: 4.

Tubulocystic renal cell carcinoma: a new radiological entity.

UNLABELLED: Tubulocystic renal cell carcinoma (TC-RCC) is a recently identified renal malignancy. While approximately 100 cases of TC-RCC have been reported in the pathology literature, imaging features have not yet been clearly described. The purpose of this review is to describe the main radiologic features of this rare sub-type of RCC on ultrasound, computed tomography (CT), and magnetic resonance imaging (MRI), based jointly on the literature and findings from a multi-institutional retrospective HIPAA-compliant review of pathology and imaging databases. Using a combination of sonographic and CT/MRI features, diagnosis of TC-RCC appeared to be strongly suggested in many cases. KEY POINTS: • Tubulocystic renal cell carcinoma is a new entity with typical imaging features • Diagnosis of tubulocystic renal cell carcinoma can be suggested preoperatively by imaging • Cystic renal lesions with high echogenicity may correspond to tubulocystic carcinoma.

[Cancer genetic screening for patient with multiple renal tumors: What is the current practice for what results?]. / Dépistage oncogénétique des patients atteints de tumeurs rénales multiples : quelle pratique pour quels résultats ?

AIM: To evaluate in a high volume center the practice and the performance of cancer genetic screening for patients with multiple renal tumors without a predisposition to kidney tumors known at the time of surgery. METHOD: All patients treated for multiple renal tumors from January 2000 to December 2013 in our center were included. Patients with a family history of renal cell carcinoma, a kidney disease or a genetic predisposition to renal cancer known at the time of surgery were excluded from the analysis. Our list of patients was retrospectively compared to the records from PREDIR (PREDisposition to Kidney Tumors) center of Île-de-France, which regionally centralizes the care of patients with kidney tumors associated with a genetic predisposition. RESULTS: One hundred and thirty-six patients were included. Twenty-six patients of 136 (19%) were referred to PREDIR center: 23 followed the screening and 3 did not show up in consultation. Of the 23 patients screened, three genetic predispositions to kidney tumors were identified (13%). Of the 95 patients with synchronous tumors, 48% with more than 3 tumors benefited from cancer genetics investigation against 13% of those presenting only two tumors. CONCLUSION: Our study shows that cancer genetic investigations are not routinely offered to patients with multiple kidney tumors, conversely to existing guidelines. Urologists must be aware of this screening. LEVEL OF EVIDENCE: 4.

RANK/OPG ratio of expression in primary clear-cell renal cell carcinoma is associated with bone metastasis and prognosis in patients treated with anti-VEGFR-TKIs.

BACKGROUND: Bone metastases (BMs) are associated with poor outcome in metastatic clear-cell renal carcinoma (m-ccRCC) treated with anti-vascular endothelial growth factor tyrosine kinase inhibitors (anti-VEGFR-TKIs). We aimed to investigate whether expression in the primary tumour of genes involved in the development of BM is associated with outcome in m-ccRCC patients treated with anti-VEGFR-TKIs. METHODS: Metastatic clear-cell renal cell carcinoma patients with available fresh-frozen tumour and treated with anti-VEGFR-TKIs. Quantitative real-time PCR (qRT-PCR) for receptor activator of NF-kB (RANK), RANK-ligand (RANKL), osteoprotegerin (OPG), the proto-oncogene SRC and DKK1 (Dickkopf WNT signalling pathway inhibitor-1). Time-to-event analysis by Kaplan-Meier estimates and Cox regression. RESULTS: We included 129 m-ccRCC patients treated between 2005 and 2013. An elevated RANK/OPG ratio was associated with shorter median time to metastasis (HR 0.50 (95% CI 0.29-0.87); P=0.014), shorter time to BM (HR 0.54 (95% CI 0.31-0.97); P=0.037), shorter median overall survival (mOS) since initial diagnosis (HR 2.27 (95% CI 1.44-3.60); P=0.0001), shorter median progression-free survival (HR 0.44 (95% CI 0.28-0.71); P=0.001) and mOS (HR 0.31 (95% CI 0.19-0.52); P<0.0001) on first-line anti-VEGFR-TKIs in the metastatic setting. Higher RANK expression was associated with shorter mOS on first-line anti-VEGFR-TKIs (HR 0.46 (95% CI 0.29-0.73); P=0.001). CONCLUSIONS: RANK/OPG ratio of expression in primary ccRCC is associated with BM and prognosis in patients treated with anti-VEGFR-TKIs. Prospective validation is warranted.

Single-nucleotide polymorphisms associated with outcome in metastatic renal cell carcinoma treated with sunitinib.

BACKGROUND: There are no validated markers that predict response in metastatic renal cell cancer (RCC) patients treated with sunitinib. We aim to study the impact of single-nucleotide polymorphisms (SNPs) that have recently been proposed as predictors of outcome to anti-VEGF-targeted therapy in metastatic RCC in an independent cohort of patients. METHODS: We genotyped 16 key SNPs in 10 genes involved in sunitinib pharmacokinetics, pharmacodynamics and VEGF-independent angiogenesis in patients with metastatic clear-cell RCC treated with sunitinib as the first-line targeted therapy. Association between SNPs, progression-free survival (PFS) and overall survival (OS) were studied by multivariate Cox regression using relevant clinical factors associated with PFS and OS as covariates. RESULTS: In a series of 88 patients, both PFS and OS were associated significantly with SNP rs1128503 in ABCB1 (P=0.027 and P=0.025), rs4073054 in NR1/3 (P=0.025 and P=0.035) and rs307821 in VEGFR3 (P=0.032 and P=0.011). Progression-free survival alone was associated with rs2981582 in FGFR2 (P=0.031) and rs2276707 in NR1/2 (P=0.047), whereas OS alone was associated with rs2307424 in NR1/3 (P=0.048) and rs307826 in VEGFR3 (P=0.013). CONCLUSION: Our results confirm former communications regarding the association between SNPs in ABCB1, NR1/2, NR1/3 and VEGFR3 and sunitinib outcome in clear-cell RCC. Prospective validation of these SNPs is now required.

Mucormycosis as a rare cause of severe gastrointestinal bleeding after multivisceral transplantation.

Mucormycosis, an emerging fungal infection in solid organ transplant patients, is mostly located in rhino-orbito-cerebral, pulmonary, and cutaneous areas, or disseminated with poor prognosis. A 4-year-old girl with chronic intestinal pseudo-obstruction syndrome underwent a modified multivisceral transplantation, including half of the stomach, the duodeno-pancreas, the small bowel, and the right colon. On postoperative day 5, a digestive perforation was suspected. Surgical exploration found a small necrotic area on the native stomach, which was externally drained. The next day, massive gastric bleeding occurred. During the emergency laparotomy, 2 hemorrhagic ulcers were found and resected from the transplanted stomach. Pathology and fungal culture showed mucormycosis caused by Lichtheimia (formerly Absidia) ramosa in both the transplanted and native stomach. High-dose intravenous liposomal amphotericin B was immediately started. No other site of fungal infection was found. The child recovered, and 3 years after transplantation, is alive and well, off parenteral nutrition. The originality of this case is the very early presentation after transplantation, the unusual site, and the complete recovery after rapid medico-surgical management. The origin of the fungus and treatment are discussed.

[Histopathology of coeliac disease]. / Le diagnostic histologique de la maladie cœliaque.

Coeliac disease is a common disease, affecting 1% of the population. Clinical manifestations are multiple. The diagnosis requires serologic testing and a duodenal biopsy that shows the characteristic findings of intraepithelial lymphocytosis, crypt hyperplasia and villous atrophy, and a positive response to a gluten-free diet. In most patients, the histological diagnosis is easily established. Pitfalls in the pathological diagnosis include a poorly orientated biopsy specimen, either an inadequate biopsy sampling in patients with patchy villous atrophy and the other causes of villous atrophy. A non-response to the gluten-free diet needs to reassess first, the initial diagnosis, second to be sure of the gluten-free diet adherence, and third, to exclude malignant complications such as refractory celiac disease or enteropathy-associated T-cell lymphoma.

Factors associated with partial and complete regression of fetal lung lesions.

OBJECTIVE: A decrease in the volume of congenital pulmonary malformations (CPM) can be observed on prenatal ultrasonography, but the underlying mechanism for this phenomenon is unknown. Our objective was to identify factors associated with the prenatal reduction in size of cystic and/or hyperechoic lung lesions. METHODS: This was a retrospective study of cases with a prenatal diagnosis of hyperechoic and/or cystic lung lesion. The extent of reduction in lesion size was calculated from ultrasound measurements. Clinical, ultrasound, radiological and histological data were tested for their relationship with prenatal CPM reduction. RESULTS: In a 4-year period, 36 patients were referred with a cystic and/or hyperechoic fetal lung lesion diagnosed at a mean gestational age of 23.4 weeks. The lesions were cystic in 16 cases (44%), hyperechoic in 12 (33%) and both in eight (22%). The malformation was no longer visible before birth (apparent disappearance) in nine cases (25%), shrank by 18-90% in 15 (42%) and did not reduce in 12 (33%). Findings on postnatal computed tomography were always abnormal. Isolated hyperechoic lesions were significantly more likely to shrink in utero. The mean reductions were 79%, 35% and 19%, for isolated hyperechoic, cystic and mixed lesions, respectively (P=0.001). Only 8% of hyperechoic lesions demonstrated no volume reduction, as compared to 50% and 42% of cystic and mixed lesions, respectively (P=0.03). Greater gestational age at birth was also associated with a decrease in the incidence of malformations (P=0.02). In cases that underwent surgery, hyperechoic lesions were linked to a variety of pathological diagnoses, whereas cystic lesions were all described histologically as congenital cystic adenomatoid malformations. CONCLUSIONS: Prenatal size reduction of fetal lung malformations is associated with isolated hyperechogenicity and greater gestational age at birth. This might result from the resumption of normal lung development after local disruption of lung growth.

ABCC8 and KCNJ11 molecular spectrum of 109 patients with diazoxide-unresponsive congenital hyperinsulinism.

BACKGROUND: Congenital hyperinsulinism (CHI) is characterised by an over secretion of insulin by the pancreatic ß-cells. This condition is mostly caused by mutations in ABCC8 or KCNJ11 genes encoding the SUR1 and KIR6.2 subunits of the ATP-sensitive potassium (K(ATP)) channel. CHI patients are classified according to their responsiveness to diazoxide and to their histopathological diagnosis (either focal, diffuse or atypical forms). Here, we raise the benefits/limits of the genetic diagnosis in the clinical management of CHI patients. METHODS: ABCC8/KCNJ11 mutational spectrum was established in 109 diazoxide-unresponsive CHI patients for whom an appropriate clinical management is essential to prevent brain damage. Relationships between genotype and radiopathological diagnosis were analysed. RESULTS: ABCC8 or KCNJ11 defects were found in 82% of the CHI cases. All patients with a focal form were associated with a single K(ATP) channel molecular event. In contrast, patients with diffuse forms were genetically more heterogeneous: 47% were associated with recessively inherited mutations, 34% carried a single heterozygous mutation and 19% had no mutation. There appeared to be a predominance of paternally inherited mutations in patients diagnosed with a diffuse form and carrying a sole K(ATP) channel mutation. CONCLUSIONS: The identification of recessively inherited mutations related to severe and diffuse forms of CHI provides an informative genetic diagnosis and allows prenatal diagnosis. In contrast, in patients carrying a single K(ATP) channel mutation, genetic analysis should be confronted with the PET imaging to categorise patients as focal or diffuse forms in order to get the appropriate therapeutic management.

Enteropathy-associated T-cell lymphoma: a review on clinical presentation, diagnosis, therapeutic strategies and perspectives.

INTRODUCTION: Enteropathy-associated T-cell lymphoma (EATL) is a rare complication of celiac disease (<1% of lymphomas) and has a poor prognosis. METHODS: International literature review with PubMed search (up to January 2009) of pathophysiological, clinical and therapeutic data. RESULTS: EATL is found in patients with a mean age of 59 years, often with a complication that signals its diagnosis. Refractory celiac disease (RCD), equivalent to low-grade intraepithelial T-cell lymphoma, could be an intermediary between celiac disease and high-grade invasive T-cell lymphoma. The median survival is 7 months, with no significant difference between stages; the cumulative 5-year survival is less than 20%. The poor prognosis is determined by disease that has often spread before it is diagnosed (50%), multifocal involvement of the small bowel (50%), poor general health status and undernutrition, and recurrence of complications (infections, perforations, gastrointestinal haemorrhages, occlusions), thus delaying the chemotherapy and contributing to frequent chemotherapy resistance. There is currently no effective and consensual treatment: preventive surgery for complications is controversial, and the results of chemotherapy are disappointing. The classic CHOP protocol (combination of doxorubicin-cyclophosphamide-vincristine-prednisone) does not have satisfactory results and survival remains poor, especially in patients with underlying RCD. High-dose chemotherapy with autotransplantion seems to only improve the prognosis in localised forms. Allogeneic bone marrow transplantation was not evaluated. In all, 1/3 of patients, being unfit for treatment, die before 3 months and half of treated patients stop chemotherapy prematurely due to inefficacy, intolerance and/or complications. CONCLUSION: Improvement of the prognosis requires collaboration in order to compose a national cohort, to evaluate new diagnostic and therapeutic strategies and to define prognostic factors.

[Papillary renal cell carcinoma: morphological subtypes, clinical and histopathological considerations]. / Particularités pronostiques, histopathologiques, génétiques et thérapeutiques du carcinome à cellules rénales tubulopapillaire.

PURPOSE: We reviewed papillary renal cell carcinoma (PRCC) epidemiology, radiological and clinical presentations, and specific features of morphological subtypes focusing on genetic defects, risk of local and metastatic recurrence and frequency of multifocality. MATERIALS AND METHODS: The MEDLINE database of the US National Library of Medicine was searched for pertinent studies. RESULTS: According to multivariate analyses, PRCC histology was not retained as a prognostic factor. Reported rates of multifocality in PRCC are 22 to 41% but distinction between histological subtype or hereditary forms are barely detailed. Multifocality frequency is independent of size, stage or grade and is not associated with ipsilateral or controlateral recurrence or death from RCC. Thus, PRCC multifocality is not an argument against nephron-sparing surgery. Antiangionenic therapies are being evaluated for the Metastatic PRCC. CONCLUSION: According to the literature, specific prognostic features of PRCC remain controversial due to the lack of distinction between different PRCC subtypes. Genomic and cytogenetic characterizations have been used to establish an evolving classification of PRCC subtypes and may be a source of new markers that will eventually enable us to precise prognosis and identify targets for new adjuvant therapies.

Chromosome 11p15 paternal isodisomy in focal forms of neonatal hyperinsulinism.

CONTEXT: Focal forms of congenital hyperinsulinism are due to a constitutional heterozygous mutation of paternal origin in the ABCC8 gene, more often than the KCNJ11 gene, located in the 11p15.1 region. This mutation is associated with the loss of the maternally inherited 11p15.1 to 11p15.5 region in the lesion. We investigated the possible occurrence of a compensatory duplication of the paternal 11p15.1-11p15.5 region. MATERIALS AND METHODS: A combined immunohistochemistry and fluorescent in situ hybridization study on beta-cell interphase nuclei with probes covering two genes located in this region (ABCC8 and CDKN1C genes) was performed in four cases of focal forms of hyperinsulinism. RESULTS: beta-Cells in the lesions of four cases of focal congenital hyperinsulinism were diploid for chromosomes 11 and 13. The 11p15.1 to 11p15.2 and 11p15.4 to 11p15.5 regions containing ABCC8 and CDKN1C genes, respectively, were present with two copies. Loss of the maternal allele was confirmed in these focal lesions with microsatellite markers flanking the ABCC8 and CDKN1C genes, whereas a heterozygous mutation in the ABCC8 gene was inherited from the father. CONCLUSIONS: There is a duplication of the paternal allele on chromosome 11 in the focal forms of hyperinsulinism lesion. The paternal isodisomy observed rendered the beta-cells homozygous for ABCC8 mutation and harbored a K-channel defect in the lesion similar to that observed in diffuse forms of congenital hyperinsulinism.

Liver hepatoblastoma and multiple OXPHOS deficiency in the follow-up of a patient with methylmalonic aciduria.

A boy who was diagnosed with methylmalonic aciduria (MMA) at the age of 10 days developed persistent hepatomegaly and raised transaminases from the age of 4 years. He was subsequently diagnosed with Leigh syndrome and required a kidney transplantation for end-stage renal failure. A massive hepatoblastoma led to his death by the age of 11 years. Methylmalonyl-CoA mutase activity was undetectable on both cultured skin fibroblasts and kidney biopsy and multiple respiratory chain deficiency was demonstrated in the kidney. Mitochondrial dysfunction and/or post-transplant immunosuppressive therapy should be considered as a possible cause of liver cancer in this patient.